Inborn errors of metabolism offer an opportunity to investigate the effects of an enzymatic lesion on cellular metabolism and biosynthetic capacities. Our goal is to understand at the cellular level the mechanism by which heritable diseases give rise to abnormal phenotypes. Inborn errors of metabolism will be invetigated in cell culture since this system provides a means of studying cellualr metabolism in a controlled external environment unaffected by interactions with other cell types. Moreover, molecular mechanisms are more easily investigated in this model. For example, cell hybridization using Sendai virus has been used in our laboratory to study complementation, that is restoration of enzyme activity, when two different mutants having the same enzymatic deficiency are fused together forming a heterokaryon. Cell culture provides an opportunity to study enzyme regulation in normal and mutant cells by altering the composition of the medium to either accentuate or mitigate the enzymatic acitivity. For example, the cys(e)ine content of medium affects the activity of certain membrane bound enzymes including the branched chainketo acid (BCKA) decarboxylase. These studies might not only contribute to a better understanding of enzyme control, but also might prove useful in detecting carriers of the mutant gene and in developeing rational methods of therapy. Comparison between the biochemical may contribute to an understanding of the variable expression and genetic heterogeneity observed with many of these disorders.